Transition-Metal-Free Borylation of Alkyl Iodides via a Radical Mechanism

英文原文与中文译文逐段对照 · English original with Chinese translation

Qianyi Liu, ${}^{ \dagger }$ Junting Hong, ${}^{ \dagger }$ Beiqi Sun, ${}^{ \dagger }$ Guangcan Bai, ${}^{ \ddagger }$ Feng Li, ${}^{ \ddagger }$ Guoquan Liu, ${}^{ \ddagger }$ D Yang Yang, ${}^{ \ddagger }$ O and Fanyang Mo**, I . I . I . I . I . I . I . I . I . I . I . I

刘千一，${}^{ \dagger }$ 洪钧婷，${}^{ \dagger }$ 孙北奇，${}^{ \dagger }$ 白广灿，${}^{ \ddagger }$ 李枫，${}^{ \ddagger }$ 刘国权，${}^{ \ddagger }$ 杨阳，${}^{ \ddagger }$ 以及莫凡洋**，I. I. I. I. I. I. I. I. I. I. I. I

${}^{ \dagger }$ Department of Energy and Resources Engineering, College of Engineering, Peking University, Beijing 100871, China

${}^{ \dagger }$ 北京大学工学院能源与资源工程系，北京 100871，中国

${}^{ \ddagger }$ State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100871, China

${}^{ \ddagger }$ 北京大学药学院天然药物及仿生药物国家重点实验室，北京 100871，中国

${}^{\text{ § }}$ Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United States “Donghai High-tech Industrial Development Zone, Donghai County, Jiangsu Province 222000, China

${}^{\text{ § }}$ 加利福尼亚理工学院化学与化学工程系，帕萨迪纳，加利福尼亚 91125，美国 “江苏省东海县东海高新技术产业开发区，222000，中国

(c) Supporting Information

(c) 支持信息

ABSTRACT: We describe an operationally simple transition-metal-free borylation of alkyl iodides. This method uses commercially available diboron reagents as the boron source and exhibits excellent functional group compatibility. Furthermore, a diverse range of primary and secondary alkyl iodides could be effectively transformed to the corresponding alkylboronates in excellent yield. Mechanistic investigations suggest that this borylation reaction proceeds through a single-electron transfer mechanism featuring the generation of an alkyl radical intermediate.

摘要:我们描述了一种操作简单的无过渡金属催化的烷基碘硼化反应。该方法使用市售的双硼试剂作为硼源，具有出色的官能团兼容性。此外，各种伯烷基碘和仲烷基碘都能以优异的产率有效地转化为相应的硼酸烷基酯。机理研究表明，该硼化反应通过单电子转移机理进行，其特征是生成烷基自由基中间体。

Alkylboronic acids and esters represent highly versatile building blocks in transition-metal-catalyzed cross-coupling reactions and various functional group transformations. ${}^{1,2}$ Additionally, the alkylboronic acid motif itself is frequently found in clinically important drugs (e.g., bortezomib) ${}^{3}$ as well as agents used in boron neutron capture therapy (BNCT) of cancer. ${}^{4}$ Conventional methods for the preparation of these compounds include electrophilic borylation of organolithium or Grignard reagents, ${}^{5}$ hydroboration of olefins, ${}^{6}$ and transition-metal-catalyzed $\mathrm{C} - \mathrm{H}$ borylation. ${}^{7}$ Despite their synthetic utility, these methods suffer from significant limitations, including low functional group compatibility and/or moderate regioselectivity. In recent years, transition-metal-catalyzed borylation of alkyl halides has emerged as a new approach for the synthesis of alkylboronates. ${}^{8}$ To date, a variety of transition-metal catalysts based on Cu, ${}^{9}\mathrm{{Ni}},{}^{10}\mathrm{{Pd}},{}^{11} \; \mathrm{{Fe}},{}^{12}\mathrm{{Mn}},{}^{13}\mathrm{{Zn}},{}^{14}$ and ${\mathrm{{Ag}}}^{15}$ have been used for the borylation of alkyl halides (Scheme 1a). Although these methods have found many applications, the need to fine-tune the activity of the transition-metal catalyst through a tedious survey of supporting ligands is undesirable. Furthermore, a number of these processes involve the use of air-sensitive catalysts or reagents (e.g., ${\mathrm{{EtMgBr}}}^{{12}\mathrm{a},{13}}$ and $t - {\mathrm{{BuLi}}}^{{12}\mathrm{\;b}}$ ), thereby limiting the further adaptation of these methods by the synthetic community.

硼酸烷基酯和硼酸酯在过渡金属催化的交叉偶联反应和各种官能团转化中是非常通用的结构单元。${}^{1,2}$ 此外，硼酸烷基酯结构本身在临床上重要的药物(如硼替佐米)${}^{3}$ 以及用于癌症硼中子俘获疗法(BNCT)的药物中经常出现。${}^{4}$ 制备这些化合物的传统方法包括有机锂试剂或格氏试剂的亲电硼化反应，${}^{5}$ 烯烃的硼氢化反应，${}^{6}$ 以及过渡金属催化的$\mathrm{C} - \mathrm{H}$ 硼化反应。${}^{7}$ 尽管它们具有合成实用性，但这些方法存在显著局限性，包括官能团兼容性低和/或区域选择性中等。近年来，过渡金属催化的卤代烷硼化反应已成为合成硼酸烷基酯的一种新方法。${}^{8}$ 迄今为止，多种基于铜的过渡金属催化剂，${}^{9}\mathrm{{Ni}},{}^{10}\mathrm{{Pd}},{}^{11} \; \mathrm{{Fe}},{}^{12}\mathrm{{Mn}},{}^{13}\mathrm{{Zn}},{}^{14}$ 以及${\mathrm{{Ag}}}^{15}$ 已用于卤代烷的硼化反应(方案 1a)。尽管这些方法有许多应用，但通过繁琐的配体筛选来微调过渡金属催化剂的活性是不可取的。此外，其中一些过程涉及使用对空气敏感的催化剂或试剂(如${\mathrm{{EtMgBr}}}^{{12}\mathrm{a},{13}}$ 和$t - {\mathrm{{BuLi}}}^{{12}\mathrm{\;b}}$)，从而限制了合成界对这些方法的进一步应用。

During the past several years, transition-metal-free boryla-tion has been developed as a useful method for the preparation of a wide range of organoboron compounds. ${}^{16}$ Since the pioneering work of Wang in 2010, ${}^{17}$ numerous transition-metal-free aromatic borylation protocols have been developed, allowing for the conversion of anilines, ${}^{18}$ aryl (pseudo)- halides, ${}^{19}$ and aryl carboxylates ${}^{20}$ into aryl boronates. In contrast, transition-metal-free borylation of alkyl substrates remains largely underdeveloped. To date, the scope of aliphatic substrates is limited to carboxylic acid derivatives ${}^{21}$ and amine derivatives. ${}^{22}$ We note that those alkyl substrates have to be “activated” prior to the execution of borylation. Specifically, carboxylic acids are transformed into the corresponding $N$ - hydroxyphthalimide (NHPI) esters, ${}^{21}$ and amines are converted into their Katritzky pyridinium salts in order for the borylation to occur. ${}^{22}$ Thus, the direct use of abundant and easily available alkyl halides for borylation without the need of preactivation is very appealing. Herein, we describe such a protocol for the transition-metal-free borylation of an array of alkyl iodides, including both primary and secondary alkyl substrates. This method operates under mild reaction conditions and uses bench stable, widely available pinacol diboron $\left( {{\mathrm{B}}_{2}{\text{ pin }}_{2}}\right)$ for the borylation of primary alkyl iodides (Scheme 1c). During the preparation of this manuscript, the Studer group disclosed an elegant photochemical protocol for the transition-metal-free borylation of alkyl iodides. ${}^{23}$ In contrast to our method, more expensive catechol diboron $\left( {{\mathrm{B}}_{2}{\mathrm{{cat}}}_{2}}\right)$ was found to be optimal for Studer’s photochemical borylation. Due to the chromatographic instability of catechol boronates, an additional step was required to convert catechol boronates to pinacol boronates for isolation.

在过去几年中，无过渡金属硼化反应已发展成为一种制备多种有机硼化合物的有用方法。${}^{16}$ 自2010年王的开创性工作以来，${}^{17}$ 已开发出许多无过渡金属的芳香硼化反应方案，可将苯胺、${}^{18}$ 芳基(伪)卤化物、${}^{19}$ 和芳基羧酸盐 ${}^{20}$ 转化为芳基硼酸酯。相比之下，无过渡金属的烷基底物硼化反应在很大程度上仍未得到充分发展。迄今为止，脂肪族底物的范围仅限于羧酸衍生物 ${}^{21}$ 和胺衍生物。${}^{22}$ 我们注意到，这些烷基底物在进行硼化反应之前必须进行“活化”。具体而言，羧酸被转化为相应的 $N$ - 羟基邻苯二甲酰亚胺(NHPI)酯，${}^{21}$ 胺被转化为其Katritzky吡啶盐以便发生硼化反应。${}^{22}$ 因此，直接使用丰富且易于获得的烷基卤化物进行硼化反应而无需预活化非常有吸引力。在此，我们描述了一种用于一系列烷基碘化物(包括伯烷基和仲烷基底物)的无过渡金属硼化反应的方案。该方法在温和的反应条件下运行，并使用易于储存、广泛可得的频哪醇二硼 $\left( {{\mathrm{B}}_{2}{\text{ pin }}_{2}}\right)$ 对伯烷基碘化物进行硼化反应(方案1c)。在撰写本手稿期间，Studer小组公开了一种用于烷基碘化物无过渡金属硼化反应的优雅光化学方案。${}^{23}$ 与我们的方法相比，发现更昂贵的儿茶酚二硼 $\left( {{\mathrm{B}}_{2}{\mathrm{{cat}}}_{2}}\right)$ 对Studer的光化学硼化反应是最佳的。由于儿茶酚硼酸酯的色谱不稳定性，需要额外的步骤将儿茶酚硼酸酯转化为频哪醇硼酸酯以便分离。

Scheme 1. Borylation of Alkyl Halides

方案1. 烷基卤化物的硼化反应

(a) Transition-metal catalyzed borylation of alkyl (pseudo)halides

(a) 过渡金属催化的烷基(拟)卤化物的硼化反应

X = CI, Br, I, OTs

X = Cl、Br、I、OTs

(b) Photoinduced borylation of alkyl iodides

(b) 烷基碘化物的光致硼化反应

(c) Base-assisted transition-metal-free borylation of alkyl halides (this work)

(c) 碱辅助的无过渡金属的烷基卤化物硼化反应(本研究)

• Transition-metal-free, photo-free - Not sensitive to air or moisture

• 无过渡金属、无光 - 对空气或湿气不敏感

• High functional group tolerance - Simple and practical procedure

• 高官能团耐受性 - 操作简单实用

Received: June 5, 2019

收到日期:2019年6月5日

We commenced our study by investigating the borylation of octyl iodide (1a) under transition-metal-free conditions using pinacol diboron $\left( {{\mathrm{B}}_{2}{\mathrm{{pin}}}_{2}}\right)$ as the borylating reagent (Table 1). After extensive optimization, we found that the treatment of 1a with 4 equiv of ${\mathrm{B}}_{2}{\text{ pin }}_{2}$ in the presence of 2 equiv of $t$ -BuOLi in $\mathrm{{MeOH}}\left( {{0.5}\mathrm{M}}\right)$ at ${65}^{ \circ }\mathrm{C}$ for ${12}\mathrm{\;h}$ afforded the corresponding boronate $2\mathrm{a}$ in 70% yield (entry 1). Other solvents such as DMF or ${\mathrm{{CH}}}_{2}{\mathrm{{Cl}}}_{2}$ proved less effective (Table 1, entries 2 and 3, and Table S1). Further study showed that the addition of a small amount of water provided a higher yield (87%) of 2a (entry 4). We postulated that the addition of water overcame the heterogeneity issue of the current process and thus enhanced the yield of the borylation product. Importantly, when carried out strictly in the absence of light, this borylation reaction still provided the same yield of 2a (entry 5), thus completely ruling out the possibility of a photoinduced process. Other bases such as $\mathrm{{MeOLi}},{\mathrm{{Cs}}}_{2}{\mathrm{{CO}}}_{3}$ , and $\mathrm{{LiOH}}$ were less effective (entries 6-8). Additionally, we were able to reduce the amount of ${\mathrm{B}}_{2}{\mathrm{{Pin}}}_{2}$ to 3 equiv without affecting the yield of 2a (entry 9). The use of 2 equiv of ${\mathrm{B}}_{2}{\mathrm{{Pin}}}_{2}$ provided 2a in a slightly lower yield (60%). Furthermore, less reactive octyl bromide could also be borylated in good yields in the presence of a catalytic amount of KI or ${\mathrm{I}}_{2}$ (entries 11 and 12). Octyl chloride, octyl tosylate, and octyl mesylate were also compatible substrates under these conditions, providing borylation product 2a in low to moderate yields (entries 13-15). Finally, the transition-metal-free nature of this borylation reaction was ascertained by carrying out this transformation using reagents of high purity (Aldrich) with trace metal residue (see the Supporting Information for ICP-MS analysis of transition metal residues including Cu, Fe, Pd, Mn, Ni, and Zn in these reagents and other control experiments).

我们通过在无过渡金属条件下，使用频哪醇二硼$\left( {{\mathrm{B}}_{2}{\mathrm{{pin}}}_{2}}\right)$作为硼化试剂研究碘代辛烷(1a)的硼化反应来开始我们的研究(表1)。经过广泛优化，我们发现，在$\mathrm{{MeOH}}\left( {{0.5}\mathrm{M}}\right)$中，于${65}^{ \circ }\mathrm{C}$下，用4当量的${\mathrm{B}}_{2}{\text{ pin }}_{2}$与2当量的$t$-BuOLi处理1a ${12}\mathrm{\;h}$，可得到相应的硼酸酯$2\mathrm{a}$，产率为70%(第1项)。其他溶剂如DMF或${\mathrm{{CH}}}_{2}{\mathrm{{Cl}}}_{2}$效果较差(表1，第2项和第3项，以及表S1)。进一步研究表明，加入少量水可使2a的产率更高(87%)(第4项)。我们推测，加水克服了当前过程的不均匀性问题，从而提高了硼化产物的产率。重要的是，当严格在无光条件下进行时，该硼化反应仍能提供相同产率的2a(第5项)，从而完全排除了光致过程的可能性。其他碱如$\mathrm{{MeOLi}},{\mathrm{{Cs}}}_{2}{\mathrm{{CO}}}_{3}$和$\mathrm{{LiOH}}$效果较差(第6 - 8项)。此外，我们能够将${\mathrm{B}}_{2}{\mathrm{{Pin}}}_{2}$的量减少到3当量而不影响2a的产率(第9项)。使用2当量的${\mathrm{B}}_{2}{\mathrm{{Pin}}}_{2}$得到2a的产率略低(60%)。此外，在催化量的KI或${\mathrm{I}}_{2}$存在下，活性较低的溴代辛烷也能以良好的产率进行硼化反应(第11项和第12项)。在这些条件下，氯代辛烷、对甲苯磺酸辛酯和甲磺酸辛酯也是合适的底物，可提供低至中等产率的硼化产物2a(第13 - 15项)。最后，通过使用具有痕量金属残留的高纯度试剂(Aldrich)进行该转化反应，确定了该硼化反应的无过渡金属性质(有关这些试剂中包括Cu、Fe、Pd、Mn、Ni和Zn在内的过渡金属残留的ICP-MS分析以及其他对照实验，请参阅支持信息)。

Table 1. Reaction Development

表1. 反应优化

${}^{a}$ Entries 1-3, solvent $1\mathrm{\;{mL}}$ ; entries 4-12, solvent ${0.85}\mathrm{\;{mL}},{\mathrm{H}}_{2}\mathrm{O}$ (10 $\mu \mathrm{L}$ ), $\mathrm{{KI}}$ (0.2 equiv), ${\mathrm{I}}_{2}$ (0.2 equiv). ${}^{b}\mathrm{{GC}}$ yield using decane as an internal standard. Isolated yield is shown in parentheses. ${}^{c}$ In the dark. ${}^{d}\mathrm{{MeOLi}}$ as the base. ${}^{e}{\mathrm{{Cs}}}_{2}{\mathrm{{CO}}}_{3}$ as the base. ${}^{f}\mathrm{{LiOH}} \cdot {\mathrm{H}}_{2}\mathrm{O}$ as the base. ${}^{g}{\mathrm{\;B}}_{2}{\mathrm{{pin}}}_{2}$ (3 equiv), $t$ -BuOLi (1.5 equiv). ${}^{h}{\mathrm{\;B}}_{2}{\mathrm{{pin}}}_{2}$ (2 equiv), $t$ -BuOLi (1 equiv).

${}^{a}$ 条目1 - 3，溶剂 $1\mathrm{\;{mL}}$ ；条目4 - 12，溶剂 ${0.85}\mathrm{\;{mL}},{\mathrm{H}}_{2}\mathrm{O}$ (10 $\mu \mathrm{L}$ )，$\mathrm{{KI}}$ (0.2当量)，${\mathrm{I}}_{2}$ (0.2当量)。${}^{b}\mathrm{{GC}}$ 使用癸烷作为内标物的产率。括号内为分离产率。${}^{c}$ 在黑暗中。${}^{d}\mathrm{{MeOLi}}$ 作为碱。${}^{e}{\mathrm{{Cs}}}_{2}{\mathrm{{CO}}}_{3}$ 作为碱。${}^{f}\mathrm{{LiOH}} \cdot {\mathrm{H}}_{2}\mathrm{O}$ 作为碱。${}^{g}{\mathrm{\;B}}_{2}{\mathrm{{pin}}}_{2}$ (3当量)，$t$ -BuOLi (1.5当量)。${}^{h}{\mathrm{\;B}}_{2}{\mathrm{{pin}}}_{2}$ (2当量)，$t$ -BuOLi (1当量)。

With the optimized reaction conditions in hand, we next examined the substrate scope of this metal-free-borylation reaction (Scheme 2). A series of unactivated primary and secondary alkyl iodides/bromides were converted to the corresponding alkyl boronates in excellent yields. In general, primary alkyl iodides were more reactive relative to primary alkyl bromides and secondary alkyl iodides. An array of functional groups, including less reactive halides (2i-k), an alcohol (2l), a phenol (2m), ethers (2n and 2o), an amide (2p), an ester (2r), and a sulfonyl group (2t) were compatible with this method. Free alcohol and free phenol containing substrates were challenging in previously developed Cu-, Ni-, ${}^{10}$ Pd-, ${}^{11}$ Fe-, ${}^{12}$ and Mn-catalyzed ${}^{13}$ borylation reactions. Under our metal-free conditions, 1I and 1m were effectively transformed into the corresponding products, suggesting that this metal-free process is complementary to those previously developed ones using transition-metal catalysts. For secondary iodide substrates, the use of ${\mathrm{B}}_{2}{\mathrm{{cat}}}_{2}$ as the borylation agent was more effective than ${\mathrm{B}}_{2}{\mathrm{{pin}}}_{2}$ , affording secondary borylated products in good yields (2u-2y). For these substrates, further treatment with pinacol was carried out for purification.

在掌握了优化的反应条件后，我们接下来研究了这种无金属硼化反应的底物范围(方案2)。一系列未活化的伯烷基和仲烷基碘化物/溴化物以优异的产率转化为相应的硼酸烷基酯。一般来说，伯烷基碘化物相对于伯烷基溴化物和仲烷基碘化物更具反应性。一系列官能团，包括反应性较低的卤化物(2i - k)、醇(2l)、酚(2m)、醚(2n和2o)、酰胺(2p)、酯(2r)和磺酰基(2t)都与该方法兼容。含游离醇和游离酚的底物在先前开发的铜、镍、${}^{10}$ 钯、${}^{11}$ 铁、${}^{12}$ 和锰催化的 ${}^{13}$ 硼化反应中具有挑战性。在我们的无金属条件下，1I和1m有效地转化为相应的产物，这表明这种无金属过程与先前使用过渡金属催化剂开发的过程互补。对于仲碘化物底物,使用 ${\mathrm{B}}_{2}{\mathrm{{cat}}}_{2}$ 作为硼化剂比 ${\mathrm{B}}_{2}{\mathrm{{pin}}}_{2}$ 更有效，以良好的产率得到仲硼化产物(2u - 2y)。对于这些底物，用频哪醇进一步处理以进行纯化。

Moreover, we found that when this metal-free borylation reaction was conducted in a capped vial under an atmosphere of air, the yield of the product remained unaffected, thus highlighting the practicality of this process. To further demonstrate the utility of this borylation method, a gram-scale synthesis of octyl pinacol boronate was carried out under air (eq 1). The 15 mmol scale reaction furnished 2a in 82% isolated yield, thereby demonstrating the potential of this method for the large-scale synthesis of valuable alkylboronates.

此外，我们发现当这种无金属硼化反应在密封小瓶中于空气气氛下进行时，产物的产率不受影响，从而突出了该过程的实用性。为了进一步证明这种硼化方法的实用性，在空气中进行了辛基硼酸频哪醇酯的克级合成(方程式1)。15 mmol规模的反应以82%的分离产率得到2a，从而证明了该方法在大规模合成有价值的硼酸烷基酯方面的潜力。

To gain further insight into the mechanism of this base-promoted borylation reaction, we performed a series of mechanistic investigations. First, when a commonly used radical scavenger, 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), was added under the standard conditions, only 14% of 2a was obtained (Scheme 3a). Moreover, the corresponding TEMPO-trapped product was observed by GC-MS analysis. Second, the borylation of cyclopropyl substrate $1\mathbf{z}$ and $1\mathbf{a}$ a yielded the ring-opened product $2\mathbf{z}$ and 2aa, respectively, indicating the involvement of alkyl radical intermediates in this borylation reaction (Scheme 3b). In these reactions, further borylation of the newly formed alkene took place, ${}^{24}$ and protodeborylation also occurred in the formation of $2\mathbf{z}$ . Third, we found that borylation product selectivity (yield of ${2a}/\left( \right.$ conversion of $\left. {1\mathrm{a}\text{ , yield of }2\mathrm{a}}\right)$ ) correlates well with the amount of ${\mathrm{B}}_{2}{\mathrm{{pin}}}_{2}$ added (Scheme 3c). This observation shows the desired radical borylation using ${\mathrm{B}}_{2}{\mathrm{{pin}}}_{2}$ competes with other side reactions (e.g., $\mathrm{H}$ atom abstraction) of the alkyl radical intermediate.

为了进一步深入了解这种碱促进的硼化反应的机理，我们进行了一系列机理研究。首先，在标准条件下加入常用的自由基清除剂2,2,6,6-四甲基-1-哌啶氧基(TEMPO)时，仅得到14%的2a(方案3a)。此外，通过GC-MS分析观察到了相应的TEMPO捕获产物。其次，环丙基底物$1\mathbf{z}$和$1\mathbf{a}$a的硼化反应分别生成了开环产物$2\mathbf{z}$和2aa，这表明该硼化反应涉及烷基自由基中间体(方案3b)。在这些反应中，新形成的烯烃发生了进一步的硼化反应，${}^{24}$，并且在$2\mathbf{z}$的形成过程中也发生了原硼化反应。第三，我们发现硼化产物选择性(${2a}/\left( \right.$的产率$\left. {1\mathrm{a}\text{ , yield of }2\mathrm{a}}\right)$的转化率)与加入的${\mathrm{B}}_{2}{\mathrm{{pin}}}_{2}$量密切相关(方案3c)。这一观察结果表明，使用${\mathrm{B}}_{2}{\mathrm{{pin}}}_{2}$进行的理想自由基硼化反应与烷基自由基中间体的其他副反应(例如$\mathrm{H}$原子夺取)相互竞争。

Scheme 2. Substrate Scope ${}^{a}$

方案2.底物范围${}^{a}$

${}^{a}$ Reaction conditions: alkyl halide ${10.5}\mathrm{{mmol}},{\mathrm{B}}_{2}{\mathrm{{pin}}}_{2}{1.5}\mathrm{{mmol}}(3$ equiv), $t$ -BuOLi 0.75 mmol (1.5 equiv), MeOH 0.85 mL, ${\mathrm{H}}_{2}\mathrm{O}{10\mu }\mathrm{L}$ . Isolated yields were reported. The yields in parentheses are referred to the conditions with the use of ${\mathrm{B}}_{2}{\text{ pin }}_{2}\left( {2\mathrm{{mmol}},4\text{ equiv }}\right)$ and $t$ -BuOLi (1 mmol, 2 equiv). The yields with a “GC” superscript are GC yields with decane as an internal standard. The yields with a “NMR” superscript is ${}^{1}\mathrm{H}$ NMR yield with1,1,2,2-tetrachloroethane as an internal standard. ${}^{b}{\mathrm{\;B}}_{2}{\mathrm{{cat}}}_{2}$ (4 equiv), $t$ -BuOLi (2 equiv), MeOH,80 ${}^{ \circ }\mathrm{C},{48}\mathrm{\;h}$ ; then ${\mathrm{{Et}}}_{3}\mathrm{\;N}$ (4 equiv), pinacol (4 equiv), rt,3 h.

${}^{a}$反应条件:卤代烃${10.5}\mathrm{{mmol}},{\mathrm{B}}_{2}{\mathrm{{pin}}}_{2}{1.5}\mathrm{{mmol}}(3$当量)，$t$-丁基锂0.75 mmol(1.5当量)，甲醇0.85 mL，${\mathrm{H}}_{2}\mathrm{O}{10\mu }\mathrm{L}$。报告的是分离产率。括号中的产率是指使用${\mathrm{B}}_{2}{\text{ pin }}_{2}\left( {2\mathrm{{mmol}},4\text{ equiv }}\right)$和$t$-丁基锂(1 mmol，2当量)的条件下的产率。带有“GC”上标的产率是以癸烷为内标物的GC产率。带有“NMR”上标的产率是以1,1,2,2-四氯乙烷为内标物的${}^{1}\mathrm{H}$NMR产率。${}^{b}{\mathrm{\;B}}_{2}{\mathrm{{cat}}}_{2}$(4当量)，$t$-丁基锂(2当量)，甲醇，80${}^{ \circ }\mathrm{C},{48}\mathrm{\;h}$；然后${\mathrm{{Et}}}_{3}\mathrm{\;N}$(4当量)，频哪醇(4当量)，室温，3小时。

To further probe the nature of the radical species formed during the reaction, electron paramagnetic resonance (EPR) studies were next performed (Figure 1). 5,5-Dimethyl-1- pyrroline $N$ -oxide (DMPO) was introduced as a spin-trap, as it is known to react with short-living radicals to furnish more stable and EPR detectable nitroxide radicals. ${}^{25}$ In addition to octyl iodide (1a), we also selected perfluorooctyl iodide (1a- ${\mathbf{F}}_{17}$ ) as a probe due to the very characteristic EPR signals of the resulting DMPO-trapped perfluoroalkyl species. EPR spectra were simulated using the least-squares fitting method with EasySpin (see the Supporting Information for details). On the basis of literature precedents, ${}^{26}$ radicals $\mathbf{A}$ and $\mathbf{B}$ generated by reaction of the alkyl halide substrate with ${\mathrm{B}}_{2}{\mathrm{{pin}}}_{2}, t$ -BuOLi and DMPO in MeOH are assigned to nitroxide radicals shown in Figure 1. As shown in Figure 1a, the reaction of 1a leads to a DMPO-trapped radical species featuring a triplet of doublet

为了进一步探究反应过程中形成的自由基物种的性质，接下来进行了电子顺磁共振(EPR)研究(图1)。引入5,5 - 二甲基 - 1 - 吡咯啉$N$ - 氧化物(DMPO)作为自旋捕获剂，因为已知它能与短寿命自由基反应生成更稳定且可通过EPR检测的氮氧自由基。${}^{25}$ 除了碘辛烷(1a)，我们还选择了全氟碘辛烷(1a - ${\mathbf{F}}_{17}$)作为探针，因为所得DMPO捕获的全氟烷基物种具有非常独特的EPR信号。使用EasySpin通过最小二乘法拟合方法模拟EPR光谱(详细信息见支持信息)。根据文献先例，${}^{26}$ 由卤代烃底物与${\mathrm{B}}_{2}{\mathrm{{pin}}}_{2}, t$ - BuOLi和DMPO在甲醇中反应生成的自由基$\mathbf{A}$ 和$\mathbf{B}$ 被指定为图1所示的氮氧自由基。如图1a所示，1a的反应导致形成一种DMPO捕获的自由基物种，其具有双峰三重态

Scheme 3. Preliminary Mechanistic Studies

方案3. 初步机理研究

Figure 1. Experimental (black) and simulated EPR spectra (red) of reactions with DMPO in MeOH: (a) $1\mathrm{a} + {\mathrm{B}}_{2}{\mathrm{{pin}}}_{2} + t$ -BuOLi; (b) 1a- ${\mathrm{F}}_{17} + {\mathrm{B}}_{2}{\mathrm{{pin}}}_{2} + t$ -BuOLi.

图1. 在甲醇中与DMPO反应的实验(黑色)和模拟EPR光谱(红色):(a)$1\mathrm{a} + {\mathrm{B}}_{2}{\mathrm{{pin}}}_{2} + t$ - BuOLi；(b)1a - ${\mathrm{F}}_{17} + {\mathrm{B}}_{2}{\mathrm{{pin}}}_{2} + t$ - BuOLi。

EPR signal due to the coupling with the adjacent nitrogen and hydrogen atoms highlighted in blue, showing a $g$ value of 2.0063. On the other hand, the reaction of $1\mathrm{a} - {\mathrm{F}}_{17}$ gives rise to a DMPO-trapped radical featuring a quasi-quartet EPR splitting pattern due to the inductive effect caused by the adjacent fluorine substituents. Together, these results confirmed that alkyl iodide reacts with the diboron reagent and $t$ - BuOLi to generate an alkyl radical.

由于与相邻的氮和氢原子耦合产生的EPR信号用蓝色突出显示，显示$g$ 值为2.0063。另一方面，$1\mathrm{a} - {\mathrm{F}}_{17}$ 的反应产生一种DMPO捕获的自由基，由于相邻氟取代基的诱导效应，其具有准四重态EPR分裂模式。总之，这些结果证实了碘代烷与二硼试剂和$t$ - BuOLi反应生成烷基自由基。

Furthermore, we performed density functional theory (DFT) calculations on the C-B bond formation step (see the Supporting Information for details). Previous study proposed that the Lewis base adduct of the tetraalkoxydiboron compound (ate complex in Figure 2a) is a key intermediate in borylation reactions. ${}^{27}$ We found that, compared with this ate complex, alkyl radical addition to ${\mathrm{B}}_{2}{\text{ pin }}_{2}$ is more facile, leading to INT1. Subsequent B-B bond disassociation of INT1 via TS2 provides the borylation product and the Bpin radical INT2. This boron-centered radical is then trapped by $t - {\mathrm{{BuO}}}^{ - }$ to give the $t$ -BuOBpin radical anion (INT3), which can further reduce alkyl iodide to regenerate the alkyl radical. For secondary alkyl halides, ${\mathrm{B}}_{2}{\mathrm{{cat}}}_{2}$ is more favorable than ${\mathrm{B}}_{2}{\mathrm{{pin}}}_{2}$ in this radical borylation (Figure 2b).

此外，我们对C - B键形成步骤进行了密度泛函理论(DFT)计算(详细信息见支持信息)。先前的研究提出，四烷氧基二硼化合物的路易斯碱加合物(图2a中的ate配合物)是硼化反应中的关键中间体。${}^{27}$ 我们发现，与这种ate配合物相比，烷基自由基加成到${\mathrm{B}}_{2}{\text{ pin }}_{2}$ 上更容易，生成INT1。随后INT1通过TS2进行B - B键解离，得到硼化产物和Bpin自由基INT2。然后这个以硼为中心的自由基被$t - {\mathrm{{BuO}}}^{ - }$ 捕获，生成$t$ - BuOBpin自由基阴离子(INT3)，它可以进一步还原碘代烷以再生烷基自由基。对于仲卤代烃，在这种自由基硼化反应中${\mathrm{B}}_{2}{\mathrm{{cat}}}_{2}$ 比${\mathrm{B}}_{2}{\mathrm{{pin}}}_{2}$ 更有利(图2b)。

Figure 2. Computed potential energy surface of borylation reaction.

图2. 硼化反应的计算势能面。

On the basis of our combined experimental and computational evidence as well as studies on previously developed radical borylation reactions, ${}^{{16} - {22}}$ a plausible mechanism is outlined in Scheme 4. We propose that the alkoxide first reacts with ${\mathrm{B}}_{2}{\mathrm{{pin}}}_{2}$ to produce the ate complex. This ate complex then reduces the alkyl iodide through a single-electron transfer (SET) event, affording the key alkyl radical intermediate. Then this alkyl radical adds to a free ${\mathrm{B}}_{2}{\mathrm{{pin}}}_{2}$ to give INT1 via TS1. Subsequent cleavage of the B-B bond of INT1 leads to the boryl radical (INT2) and the borylation product. Finally, INT2 is trapped by an alkoxide to afford ${\mathrm{R}}^{\prime }\mathrm{{OB}}$ pin radical anion INT3, which can also undergo single electron transfer with the alkyl iodide as described above.

基于我们的实验和计算证据，以及对先前开发的自由基硼化反应的研究，${}^{{16} - {22}}$ 方案4中概述了一个合理的机理。我们提出醇盐首先与 ${\mathrm{B}}_{2}{\mathrm{{pin}}}_{2}$ 反应生成酸根络合物。然后该酸根络合物通过单电子转移(SET)事件还原烷基碘，得到关键的烷基自由基中间体。然后该烷基自由基加成到一个游离的 ${\mathrm{B}}_{2}{\mathrm{{pin}}}_{2}$ 上，通过TS1生成INT1。随后INT1的B-B键断裂生成硼自由基(INT2)和硼化产物。最后，INT2被醇盐捕获得到 ${\mathrm{R}}^{\prime }\mathrm{{OB}}$ pin自由基阴离子INT3，它也可以如上所述与烷基碘进行单电子转移。

Scheme 4. Proposed Mechanism

方案4. 提出的机理

In summary, we have developed an operationally simple transition-metal-free borylation of alkyl iodides. This transition-metal-free borylation occurs under mild conditions, tolerates a broad range of sensitive functional groups. Moreover, it provides an effective means to convert various primary and secondary alkyl iodides to the corresponding alkyl boronates. Preliminary mechanistic investigations indicated a single-electron-transfer process is likely involved in this transition-metal-free borylation. This study affords a new avenue for generating alkyl radical from easily accessible alkyl halides using simple bases and diboron reagents. Expanding the substrate scope to include other types of alkyl halides, as well as detailed mechanism, are currently underway in our laboratory.

总之，我们开发了一种操作简单的无过渡金属的烷基碘硼化反应。这种无过渡金属的硼化反应在温和条件下进行，能耐受多种敏感官能团。此外，它提供了一种将各种伯烷基和仲烷基碘转化为相应硼酸酯的有效方法。初步机理研究表明，这种无过渡金属的硼化反应可能涉及单电子转移过程。这项研究为使用简单碱和二硼试剂从易于获得的烷基卤化物生成烷基自由基提供了一条新途径。目前我们实验室正在扩大底物范围以包括其他类型的烷基卤化物，以及详细的机理研究。

BASSOCIATED CONTENT

相关内容

Supporting Information

支持信息

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.or-glett.9b01951.

支持信息可在ACS出版物网站上免费获取，DOI: 10.1021/acs.or-glett.9b01951。

Experimental procedures, additional information, and characterization data (PDF)

实验步骤、补充信息和表征数据(PDF)

AUTHOR INFORMATION

作者信息

Corresponding Author

通讯作者

ORCID ®

开放研究者与贡献者身份识别码(ORCID)

Guoquan Liu: 0000-0003-0680-4811

刘国权:0000-0003-0680-4811

Yang Yang: 0000-0002-4956-2034

杨扬:0000-0002-4956-2034

Fanyang Mo: 0000-0002-4140-3020

莫凡洋:0000-0002-4140-3020

Notes

注释

The authors declare no competing financial interest.

作者声明不存在利益冲突。

I ACKNOWLEDGMENTS

I 致谢

We thank Prof. Lei Jiao at Tsinghua University for DFT calculation consultation. The project was supported by the Natural Science Foundation of China (Grant 21772003). We also thank Peking University for a start-up fund. This work was also partially funded by the BHP-PKU CCUS project supported by BHP Billiton.

我们感谢清华大学的焦雷教授提供的密度泛函理论(DFT)计算咨询。本项目得到了中国国家自然科学基金(项目编号:21772003)的支持。我们也感谢北京大学提供的启动资金。本研究还部分得到了必和必拓支持的必和必拓 - 北大碳捕集与封存(CCUS)项目的资助。

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